The need for novel therapies that target several stages of the viral life cycle and that may not be vulnerable to the genetic flexibility of the virus are now emphasized more than ever, primarily because of the rapid emergence of drug resistant strains of HIV- 1. The target of choice is beginning to be narrowed to the non-translated 5' region of the viral genome that contains multiple regulatory elements such as TAR, PBS, A-loop, DIS etc which are critical for viral replication and averse to mutational changes. Selective intervention of the function of these regulatory regions may have profound therapeutic potential in blocking the viral infection. We have identified a number of leading polyamide nucleotide analogs (PNA) which can successfully block the function of these targets in vitro. The major thrust of this proposal is to conjugate these leading PNAs with a number of membrane transporting peptides in order to identify the most efficient biodelivery system thus enhancing the functional efficacy of these compounds. Each PNA-peptide conjugate will be examined in-depth with respect to its uptake kinetics, functional efficacy, cytotoxicity and antiviral activity in cell cultures. The leading PNA-peptideconjugates will also be tested for their pharmacokinetic behaviour, tissue distribution and toxicological properties in animal models. This will be followed by subjecting these compounds to pre-clinical trial on hu-SCID mice model reconstructed with human PBL. These studies will provide invaluable information on this class of compounds which may help in the development of effective multiprong inhibitors of high therapeutic index. The following specific aims are proposed. Aim 1: Design and synthesis of PNA-membrane transporter peptide conjugates targeted to critical regions of HIV-1 RNA genome Aim 2: Evaluation of biodelivery and functional characterization of PNA- transporter peptide conjugates. Aim 3: Evaluation of antiviral efficacy and cytotoxicity of PNA-peptide conjugates in cell culture. Aim 4: Pharmacokinetic analysis, tissue distribution and toxicological evaluation of leading PNA-transporter peptide formulations. Aim 5: Evaluation of antiviral efficacy of PNA-peptide conjugates using SCID-hu mice model.